Synthesis and biological evaluation of novel 3,4-diaryl lactam derivatives as triple reuptake inhibitors This article is dedicated to Professor Jahyo Kang for his lifelong commitment to mentoring graduate students

Article abstract of DOI:10.1016/j.bmcl.2013.08.062

A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopamine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC ₅₀ = 14 nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed inhibition (5.17 μM-85.6 nM) for three transporters.

Full text of DOI:10.1016/j.bmcl.2013.08.062

Bioorganic & Medicinal Chemistry Letters 23 (2013) 5515–5518
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel 3,4-diaryl lactam
derivatives as triple reuptake inhibitors
Jung-eun Park a,b, Chiman Song a, Keehyun Choi a, Taebo Sim a, Bongjin Moon b, Eun Joo Roh a,
⇑
a Chemical Kinomics Research Center, Korea Institute of Science and Technology, Wolsong-gil 5, Seongbuk-gu, Seoul, Republic of Korea
b Department of Chemistry, Sogang University, Baekbeomno 35, Mapogu, Seoul, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3,4-diarylpyrrolidin-2-one was designed, prepared and evaluated as triple reuptake inhibitors
for antidepressant. Most compounds exhibited comparable in vitro efficacy as norepinephrine and dopa-
mine transporter reuptake inhibitors. Especially, 2i showed better potency than GBR-12909 (IC50 = 14 -
nM) which was used as reference compound for dopamine transporter. In addition, 2a and 2b showed
Received 25 March 2013
Revised 5 August 2013
Accepted 14 August 2013
Available online 26 August 2013
inhibition (5.17 lM–85.6 nM) for three transporters.
Ó 2013 Elsevier Ltd. All rights reserved.
This article is dedicated to Professor Jahyo
Kang for his lifelong commitment to
mentoring graduate students
Keywords:
Triple reuptake inhibitors
Monoamine
Reuptake
Depression
Antidepressant
Serotonin
Dopamine
Norepinephrine
Lactam
In general, the most powerful hypothesis of depression is re-
garded as the lack of monoaminergic neurotransmitters such as
serotonin, norepinephrine and dopamine in the synapses of central
nervous system. Most of antidepressants maintain the concentra-
tion of monoamine neurotransmitters by blocking reuptake of
monoamine neurotransmitters.1
Currently selective serotonin reuptake inhibitor (SSRI) like flu-
oxetine (Prozac)2 and selective serotonin and norepinephrine reup-
take inhibitor (SNRI) like duloxetine (Cymbalta)1,3 are the most
prevalent drugs for major depression. These drugs have less side
effects than tricyclic antidepressants (TCAs) and monoamine oxi-
dase inhibitors (MAOIs) such as lack of histamine, acetylcholine,
and alpha-adrenergic receptor antagonism.1a,3
sant therapy. In other words, the clinical unmet needs of SSRIs and
SNRIs were low remission rate and therapeutic lag associated with
their use.6
In order to overcome these problems, the researchers tried to
develop drugs with new mode of action (MOA) such as triple
monoamine reuptake inhibition.7 Our first approach began to have
a similar pharmacophore suggested from leading candidate com-
pounds such as DOV216303 (Merck, phase II),8 SEP225289
(Sepracor, phase I),9 PRC025 (Mayo clinic, preclinical)10 for depres-
sion with triple reuptake inhibition as a MOA (Fig. 1).
First series of phenethylamine compounds (1) were designed
from DOV 216303 by insertion of an ethylene group to increase
rigidity, changing nitrogen position from beta to gamma, and addi-
tion of a chiral aryl group. The number and positions of the two
chlorines in DOV 216303 was altered to different position such
as 2-chloro, 3-chloro, 4-chloro and 3,4-dichloro on the phenyl ring.
The nitrogen and ethyl group were dissociated due to the low po-
tency of series 1 (not published results: binding affinity of 4 deriv-
However SSRI4 and SNRI still have side effects such as sexual
dysfunction, weight loss or gain, and drug–drug interaction.5 The
biggest problems of these drugs are that only 65% of patients
showed efficacy with antidepressants therapy and 15% of patients
had no response to all known types of therapy.6 In addition, the
therapeutic efficacy showed only after 2–4 weeks from antidepres-
atives of structure 1 at 10
hDAT = 5.0–54.0). Then,
l
M: hSERT = 9.0–61.0, hNET = 10.0–69.0,
c-lactam scaffold (2) was designed from
structure of compounds 1 and JZAD-IV-22 (Figure 2) via ethylene
removal and carbonyl group insertion.
⇑
Corresponding author.
E-mail address: r8636@kist.re.kr (E.J. Roh).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.08.062

5516
J. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5515–5518
compounds showed better activities in norepinephrine transporter
(NET) and dopamine transporter (DAT) than serotonin transporter
(SERT).
Cl
Cl
The results of R1 group derivatization in the reuptake activities
of SERT showed good activities when the R1 group was 4-chloro-
phenyl group (2a–2c) than other substituents (Table 1). Com-
pounds, 2-chlorophenyl (2i–2l) or 3-chlorophenyl (2m–2o) on R1
groups, showed lower inhibitory activities regardless of R2 group.
In the reuptake activities of NET, naphthyl compounds on R1
(2t–2v) showed low inhibitory activities while 2-chlorophenyl
(2i–2l) or phenyl (2p–2s) on R1 group showed good activities.
The results showed different structure–activity relationship (SAR)
with reuptake activities of SERT in R1 derivatization. In the case
where R2 was derivatized, they showed same SAR with SERT inhib-
itory activities.
NH2
N
H
Cl
N
OH
DOV 216303
SEP225289
PRC 025
Figure 1. Representative leading candidate compounds as triple reuptake inhibitor.
Syntheses of initial set of biaryl
c-lactam (Scheme 1) began
with commercially available benzaldehydes 3 which involved the
nitroaldol reaction using Henry condition11 and dehydration in
one-pot. Various phenyl acetic acids 5 were esterified to give
methyl esters 6. Michael addition of b-nitrostyrenes 4 with methyl
esters 6 under basic conditions gave diarylbutanoates 7. Reduction
of the diarylbutanoates 7 with Raney nickel gave intermediate
amines and the subsequent intramolecular cyclization using so-
dium hydride lead lactam 2.
The synthesized compounds 2 were evaluated for serotonin,
norepinephrine, and dopamine neurotransmitters uptake activities
using the Neurotransmitter Transporter Uptake Assay Kit (Molecu-
lar Devices, Sunnyvale, CA, USA)13 with the FDSS6000 96-well fluo-
rescence plate reader (Hamamatsu Photonics, Hamamatsu, Japan,
Table 1).14 First approach was to contain the 3,4-dichlorophenyl
group (R2 = 3,4-dichlorophenyl) and to change various substituents
on the R1 groups (2a, 2e, 2i, 2m, 2p) like DOV 216303. But most
Most compounds in this series showed above 80% inhibitory
activities in DAT without 2-chlorophenyl in R2 group.
The compounds (2a–v) were also evaluated for their binding
affinities of serotonin, norepinephrine, or dopamine transporters
using human recombinant transporters expressed in HEK293,
MDCK or CHO-K1 cells (Table 2).15
In the binding affinities of SERT, 4-chlorophenyl (2a–d) or naph-
thyl (2t–v) on R1 group showed good activities than other substit-
uents (2e–s). All of 2-chlorophenyl on R1 (2i–2l) had low affinities
regardless of R2. On the other hand, 3-chlorophenyl (2c, 2g, 2k, 2o)
on R2 showed that reversed tendency with other substituents.
And those of NET and DAT showed similar trend as in the reup-
take activities. In the binding affinities of NET showed good po-
Cl
O
Cl
Cl
N
S
N
N
H
JZAD-IV-22
DOV216303
H
N
Cl
O
R1
R
H
NH
Cl
Rigidification
H
R2
N
H
Changing
nitrogen
position
2
1
Insertion
hydrophobilc
group
Figure 2. Design strategy of compound 2.
O
a
NO2
R2
R2
H
3
4a-d
OMe
H
N
O
R2
O
O
O
R1
R1
b
c
R1
d
OMe
6a-f
R1
NO2
OH
R2
2a-v
5
7a-v
Scheme 1. Reagents and conditions: (a) nitromethane (3 equiv), ammonium acetate (2.5 equiv), acetic acid, reflux, 49.5–76.7%;11 (b) SOCl2 (3 equiv), MeOH, 0 °C to rt, 95–
98%; (c) LDA (2 equiv), 4, THF, À78 °C,12 40–69%; (d) (i) H2, Raney Ni, EtOH/Et2O (1/1); (ii) NaH (2 equiv), toluene, 90 °C,12 34–53%.

J. Park et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5515–5518
5517
Table 1
phenyl group (2d, 2h, 2l, 2s, 2v) showed low inhibitory activities.
In the case where R2 derivatization, the results showed same trend
with reuptake activities of SERT. Especially, the 2i compound
% Inhibition of reuptake activities of biaryl c-lactam derivatives 2 at hSERT, hNET and
hDAT
R1
R2
% Inhibition (10 lM)
(R1 = 2-chlorophenyl,
R2 = 3,4-dichlorophenyl,
IC50 = 8.4 nM)
Compounds
showed more potency than GBR-12909 (IC50 = 14 nM).
In summary, new derivatives with diaryl lactam moieties were
designed and prepared as triple reuptake inhibitors for major
depression and evaluated in vitro activities using fluorescence
reuptake assay system and radioligand binding assay system.
Most of these compounds showed better potency for NET and
DAT than potency for SERT. Initial hit compounds (2a, 2b, 2i) with
comparable activities in binding and reuptake inhibition were ob-
tained for further optimization to have potent efficacy as an
antidepressant.
hSERT
hNET
hDAT
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4-Cl Ph
4-Cl Ph
4-Cl Ph
4-Cl Ph
3,4-DichloroPh
3,4-DichloroPh
3,4-DichloroPh
3,4-DichloroPh
2-Cl Ph
2-Cl Ph
2-Cl Ph
2-Cl Ph
3-Cl Ph
3-Cl Ph
3-Cl Ph
Phenyl
Phenyl
3,4-DichloroPh
4-Cl Ph
3-Cl Ph
2-Cl Ph
3,4-DichloroPh
4-Cl Ph
3-Cl Ph
2-Cl Ph
3,4-DichloroPh
4-Cl Ph
3-Cl Ph
2-Cl Ph
3,4-DichloroPh
4-Cl Ph
3-Cl Ph
3,4-DichloroPh
4-Cl Ph
3-Cl Ph
2-Cl Ph
3,4-DichloroPh
4-Cl Ph
2-Cl Ph
50.4
58.1
38.4
8.5
89.2
56.6
66.9
15.0
40.4
56.9
44.5
24.2
91.6
82.3
68.9
12.1
90.5
75.4
65.7
91.6
79.9
64.8
62.1
11.7
49.6
27.4
56.0
100.0
85.0
93.8
91.8
94.6
61.2
86.8
89.4
89.7
55.0
93.9
95.8
93.8
65.0
95.4
92.9
94.6
93.2
97.0
94.0
91.8
82.6
91.6
40.8
31.0
73.0
89.0
8.8
22.7
40.9
6.2
21.9
23.4
20.2
6.9
20.4
12.2
14.3
29.4
30.8
24.3
19.3
4.4
Acknowledgments
This work was supported by the KIST Institutional Program
(Grant No. 2E24090) from Korea Institute of Science and Technol-
ogy and the Creative Fusion Research Program from Korea
Research Council of Fundamental Science and Technology.
2q
2r
2s
2t
2u
2v
Phenyl
Phenyl
Naphthyl
Naphthyl
Naphthyl
26.3
4.5
89.0
54.0
69.0
Supplementary data
Fluoxetine
Nisoxetine
GBR-12909
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2013.08.062.
tency when R1 was 3,4-dichlorophenyl and 4-chlorophenyl. In the
case where R2 group was derivatization, the result showed good
efficacy when R2 was 4-chlorophenyl (2b, 2f, 2j, 2n, 2q, 2u) or
3,4-dichlorophenyl group (2a, 2e, 2i, 2m, 2p, 2t). On the other
hand, when R2 was 3-chlorophenyl (2c, 2g, 2k, 2o, 2r) or 2-chloro-
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c
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1376
2-Cl Ph
Imipramine
Fluoxetine
Desipramine
Clomipramine
GBR-12909
6.8
7.2
1.5
64.6
2777
14
a
b
c
Inhibition of serotonin uptake in HEK-293 cells using overexpression of human recombinant serotonin transport and [3H]Imipramin.
Inhibition of serotonin uptake in MDCK cells using overexpression of human recombinant norepinephrine transport and [3H]Nisoxetine.
Inhibition of serotonin uptake in CHO-K1 cells using overexpression of human recombinant dopamine transport and [3H]Win35428.

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